Traumatic brain injury (TBI) is the leading cause of disability in children in the U.S., with the highest risk reported in infants and young children (0-4 years old). There is a high prevalence of previous TBI among cocaine users and an association between early age at time of TBI and cocaine use in adolescence. Thus, early age at time of TBI is an important risk factor for development of addiction. Here I will propose to study the relationship between injury to the rodent brain at postnatal day 21 (pnd21), an age that approximates the toddler-aged child, neuroinflammation, and addiction to cocaine at adolescence. Cocaine and other common drugs of abuse share a mechanistic link between increasing dopaminergic transmission in the mesolimbic and mesocortical pathways and addictive behavior. Dopaminergic neurons originate in the ventral tegmental area (VTA) of the midbrain, and project to the ventral striatum, including the nucleus accumbens (NAc), and the prefrontal cortex (PFC). TBI at pnd21 reduces dopaminergic signaling in the striatum and VTA at adulthood. Such a decreased dopaminergic state may increase the likelihood for sensitivity to addiction as a mechanism to restore dopamine. What remains unclear is whether disruption to this signaling is evident during the adolescent period, where there is an established high risk of substance abuse, and the extent to which immune responses, expressed within in the acutely injured brain, alter long-term addictive behaviors. The young brain shows a profound inflammatory response to TBI; we have found that interleukin-1 related signaling is upregulated in cortical and subcortical structures within the first week after injury at pnd21. I will determine if this upregulation likewise occurs in the reward pathways, a possibility that is reinforced by studies of TBI to the adolescent brain where there is an upregulation of IL-1 cytokines and factors in the cortex and NAc. I hypothesize that traumatic injury to the developing brain produces a robust early inflammatory response in the reward pathway that enhances addictive liability to cocaine at adolescence. To test this hypothesis, Aim 1 will determine if TBI at pnd21 leads to disruption of the reward pathway and enhanced addictive liability of cocaine during subsequent brain development, utilizing a self-administration model of cocaine addiction at adolescence and adulthood, and stereology to assess dopaminergic signaling in the reward pathways. Aim 2 will evaluate inflammatory signaling in the reward pathway in the acutely injured brain, and determine if IL-1 signaling contributes to addictive liability to cocaine at adolescence. Biochemical techniques will be used to profile inflammation in the reward pathway after early age TBI. Brain-injured animals will be acutely treated with an IL-1R antagonist or vehicle to assess impact of IL-1 on addictive liability at adolescence. The data generated in these aims will broaden our understanding of age-dependent vulnerability to TBI, including mechanistic insights into long-term maladaptive behaviors including drug addiction. Such findings will contribute to a platform for optimizing recovery in the brain injured child.